Linking Alzheimer's disease to insulin resistance: the FoxO response to oxidative stress
Abstract
Oxidative stress is an important determinant not only in the pathogenesis of Alzheimer's disease (AD), but also in insulin resistance (InsRes) and diabetic complications. Forkhead box class O (FoxO) transcription factors are involved in both insulin action and the cellular response to oxidative stress, thereby providing a potential integrative link between AD and InsRes. For example, the expression of intra- and extracellular antioxidant enzymes, such as manganese-superoxide dismutase and selenoprotein P, is regulated by FoxO proteins, as is the expression of important hepatic enzymes of gluconeogenesis. Here, we review the molecular mechanisms involved in the pathogenesis of AD and InsRes and discuss the function of FoxO proteins in these processes. Both InsRes and oxidative stress may promote the transcriptional activity of FoxO proteins, resulting in hyperglycaemia and a further increased production of reactive oxygen species (ROS). The consecutive activation of c-Jun N-terminal kinases and inhibition of Wingless (Wnt) signalling may result in the formation of β-amyloid plaques and τ protein phosphorylation. Wnt inhibition may also result in a sustained activation of FoxO proteins with induction of apoptosis and neuronal loss, thereby completing a vicious circle from oxidative stress, InsRes and hyperglycaemia back to the formation of ROS and consecutive neurodegeneration. In view of their central function in this model, FoxO proteins may provide a potential molecular targ…
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GSK-3β may regulate tau toxicity through its role in metabolic signaling and activation of the FoxO class of transcription factors.
“thus, GSK-3β may regulate tau toxicity through its role in metabolic signaling and activation of the FoxO class of transcription factors (113,114).”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [114]
Cites
Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress
Kops, G. J. P. L., Dansen, T. B., Polderman, P. E., Saarloos, I., Wirtz, K. W. A., Coffer, P. J., Huang, T.-T., Bos, J. L., Medema, R. H., & Burgering, B. M. T. (2002) · Nature · doi:10.1038/nature01036 · Cited by 1,580 · see citing works
Beal, M. F. (2002) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(02)00780-3 · Cited by 763 · see citing works
Positive and Negative Regulation of Insulin Signaling by Reactive Oxygen and Nitrogen Species
Bashan, N., Kovsan, J., Kachko, I., Ovadia, H., & Rudich, A. (2009) · Physiological Reviews · doi:10.1152/physrev.00014.2008 · Cited by 542 · see citing works
Oxidative stress mediates tau-induced neurodegeneration in Drosophila
Dias-Santagata, D., Fulga, T. A., Duttaroy, A., & Feany, M. B. (2007) · Journal of Clinical Investigation · doi:10.1172/jci28769 · Cited by 318 · see citing works
The FoxO transcription factors and metabolic regulation
Nakae, J., Oki, M., & Cao, Y. (2008) · FEBS Letters · doi:10.1016/j.febslet.2007.11.025 · Cited by 176 · see citing works
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How does brain insulin resistance develop in Alzheimer's disease?
De Felice, F. G., Lourenco, M. V., & Ferreira, S. T. (2014) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2013.12.004 · Cited by 337 · see citing works
Vallée, A., Lecarpentier, Y., Guillevin, R., & Vallée, J.-N. (2017) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gmx073 · Cited by 226 · see citing works
Oxidant/Antioxidant Imbalance in Alzheimer’s Disease: Therapeutic and Diagnostic Prospects
Wojsiat, J., Zoltowska, K. M., Laskowska-Kaszub, K., & Wojda, U. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/6435861 · Cited by 221 · see citing works
Association of DNA methylation differences with schizophrenia in an Epigenome-Wide association study
Montano, C., Taub, M. A., Jaffe, A., Briem, E., Feinberg, J. I., Trygvadottir, R., Idrizi, A., Runarsson, A., Berndsen, B., Gur, R. C., et al. (2016) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2016.0144 · Cited by 180 · see citing works
Redefining neuroendocrinology: Epigenetics of brain-body communication over the life course
McEwen, B. S. (2018) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2017.11.001 · Cited by 129 · see citing works
Ambegaokar, S. S., & Jackson, G. R. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr432 · Cited by 113 · see citing works
“Dysregulated insulin signaling is strongly implicated in AD (110–112); thus, GSK-3b may regulate tau toxicity through its role in metabolic signaling and activation of the FoxO class of transcription factors (113,114).”
BackgroundCross-talk between Insulin and Wnt Signaling in Preadipocytes
Palsgaard, J., Emanuelli, B., Winnay, J. N., Sumara, G., Karsenty, G., & Kahn, C. R. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.337048 · Cited by 98 · see citing works
Zhang, L., Fang, Y., Cheng, X., Lian, Y.-J., & Xu, H.-L. (2019) · Molecular Neurobiology · doi:10.1007/s12035-018-1299-y · Cited by 88 · see citing works
Croze, M. L., & Zimmer, L. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-170857 · Cited by 78 · see citing works
- Authors
- Manolopoulos, K. N., Klotz, L.-O., Korsten, P., Bornstein, S. R., & Barthel, A.
- Affiliations
- Churchill Hospital (GB)
- Leibniz Institute of Environmental Medicine (DE)
- Universitätsmedizin Göttingen (DE)
- University Hospital Carl Gustav Carus (DE)
- Corresponding author
- Barthel, A
- Venue
- Molecular Psychiatry
- Published
- 2010-10-22
- Volume
- 15
- Issue
- 11
- Pages
- 1046-1052
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- OpenAlex
- W2069306070
- Cited by
- 150
- References
- 5
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 14 · 2023: 11 · 2022: 13 · 2021: 11 · 2020: 11 · 2019: 6 · 2018: 14 · 2017: 11 · 2016: 10 · 2015: 7 · 2014: 11 · 2013: 9 · 2012: 6
- FWCI
- 0.62
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Site cant be reached (submittedVersion)
- GRO (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Funders
- Bundesministerium für Bildung und Forschung
- Deutsche Diabetes Gesellschaft
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, insulin resistance, FOXO transcription factors, oxidative stress, reactive oxygen species, hyperglycemia, c-Jun N-terminal kinase, Wnt signaling, amyloid plaques, tau phosphorylation, apoptosis, neurodegeneration, antioxidant enzymes, gluconeogenesis, manganese superoxide dismutase, selenoprotein P
- MeSH terms
- Alzheimer Disease, Humans, Insulin Resistance, Models, Biological, Signal Transduction, Oxidative Stress, Forkhead Transcription Factors
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